title: Asymptomatic HLA-A*02:01-restricted epitopes from herpes simplex virus glycoprotein B preferentially recall polyfunctional CD8+ T cells from seropositive asymptomatic individuals and protect HLA transgenic mice against ocular herpes.
abstract: Evidence from C57BL/6 mice suggests that CD8(+) T cells, specific to the immunodominant HSV-1 glycoprotein B (gB) H-2(b)-restricted epitope (gB498-505), protect against ocular herpes infection and disease. However, the possible role of CD8(+) T cells, specific to HLA-restricted gB epitopes, in protective immunity seen in HSV-1-seropositive asymptomatic (ASYMP) healthy individuals (who have never had clinical herpes) remains to be determined. In this study, we used multiple prediction algorithms to identify 10 potential HLA-A*02:01-restricted CD8(+) T cell epitopes from the HSV-1 gB amino acid sequence. Six of these epitopes exhibited high-affinity binding to HLA-A*02:01 molecules. In 10 sequentially studied HLA-A*02:01-positive, HSV-1-seropositive ASYMP individuals, the most frequent, robust, and polyfunctional CD8(+) T cell responses, as assessed by a combination of tetramer, IFN-γ-ELISPOT, CFSE proliferation, CD107a/b cytotoxic degranulation, and multiplex cytokine assays, were directed mainly against epitopes gB342-350 and gB561-569. In contrast, in 10 HLA-A*02:01-positive, HSV-1-seropositive symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent clinical herpes disease) frequent, but less robust, CD8(+) T cell responses were directed mainly against nonoverlapping epitopes (gB183-191 and gB441-449). ASYMP individuals had a significantly higher proportion of HSV-gB-specific CD8(+) T cells expressing CD107a/b degranulation marker and producing effector cytokines IL-2, IFN-γ, and TNF-α than did SYMP individuals. Moreover, immunization of a novel herpes-susceptible HLA-A*02:01 transgenic mouse model with ASYMP epitopes, but not with SYMP epitopes, induced strong CD8(+) T cell-dependent protective immunity against ocular herpes infection and disease. These findings should guide the development of a safe and effective T cell-based herpes vaccine.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, CA 92697;
authors.forename: Xavier
authors.initials: X
authors.lastname: Dervillez
authors.forename: Huma
authors.initials: H
authors.lastname: Qureshi
authors.forename: Aziz A
authors.initials: AA
authors.lastname: Chentoufi
authors.forename: Arif A
authors.initials: AA
authors.lastname: Khan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kritzer
authors.forename: David C
authors.initials: DC
authors.lastname: Yu
authors.forename: Oscar R
authors.initials: OR
authors.lastname: Diaz
authors.forename: Chetan
authors.initials: C
authors.lastname: Gottimukkala
authors.forename: Mina
authors.initials: M
authors.lastname: Kalantari
authors.forename: Maria C
authors.initials: MC
authors.lastname: Villacres
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Scarfone
authors.forename: Denise M
authors.initials: DM
authors.lastname: McKinney
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Nesburn
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wechsler
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D058345:Asymptomatic Infections; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018139:Simplexvirus / Q000276:immunology / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology*; D055815:Young Adult
chemical_list: D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus